The primary therapeutic goal for patients with locally recurrent, locally advanced, or metastatic breast cancer is retarding the progression of cancer for as long as possible, while minimizing side effects and maintaining good quality of life. The majority of breast cancers have nuclear receptors for estrogen (ER) and/or progesterone (PR) and utilize estrogen as a major growth factor. Antagonizing estrogen to control tumor growth has been achieved in two ways: by competing for the binding site of the estrogen receptor with anti-estrogens (SERMS) or by removing estrogen by inhibiting its synthesis with aromatase (estrogen synthetase) inhibitors (AIs). Cancer cells develop resistance to SERMS such as tamoxifen (Nolvadex®) or toremifene (Fareston®) by increasing uptake of estrogens from plasma, by developing hypersensitivity to the residual level of ER stimulation and by increasing levels of estrogen synthesizing enzymes, such as aromatase, within the tumor cells as much as 3–10 fold. High in-situ, intra- and peri-tumoral estrogen levels may displace the SERM and cause clinical progression of the disease. In contrast resistance to AI therapy may also develop by causing hypersensitivity to residual and exogenous estrogens. Hence it has been hypothesized that a combination of a SERM and an AI (total estrogen blockade) might be the optimal way to treat hormone dependent breast cancer and prevent the emergence of resistance. Combining tamoxifen (SERM) with an AI (anastrozole) was one of three arms of the Phase 3 adjuvant ATAC study comparing tamoxifen to anastrozole and the combination. Interestingly the combination arm performed worst of all, the hypothesis being that in the low estrogenic environment created by the AI, tamoxifen exaggerates its known partial estrogenic signal. It has been hypothesized that if a SERM with less inherent estrogenicity than tamoxifen were combined with an AI the therapy would be more successful. Similar to letrozole and tamoxifen combined in another trial, a 27% reduction in plasma levels of anastrozole was also detected. BioMedicines is currently testing that hypothesis in a clinical Phase 3 trial combining the experimental and currently unapproved AI atamestane and the approved SERM toremifene and comparing that combination to the approved AI letrozole. Toremifene is clinically equi-effective against tamoxifen in treatment naïve patients, but is 40-fold less estrogenic in a low estrogen environment in preclinical models. Atamestane is a steroidal AI, which has shown a median time to progression of 8 months, with 10% of the patients progression-free at 36 months, in tamoxifen-resistant patients. It is well tolerated and may have advantages over the non-steroidal AI's in terms of efficacy and toxicity. Atamestane also does not interact pharmacologically with the toremifene. The control arm is letrozole, currently the most effective single agent endocrine therapy for postmenopausal women. Patients eligible for our study are required to have positive receptor status, have measurable tumor lesions and to have received the last dose of adjuvant hormonal therapy at least 12 months prior to enrollment. Our trial strategy is thus similar to the total androgen blockade approach to prostate cancer where this approach has been successful.